Inflammatory reactions and associated pain can be induced by prostaglandins. Inflammation can be reduced by inhibiting prostaglandin biosynthesis. Most non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, inhibit prostaglandin synthesis by inhibiting cyclooxygenase, a key regulated enzyme in synthesis of 20 carbon eicosenoids, including prostaglandin E2 (PGE.sub.2), from arachidonic acid. However, complete inhibition of prostaglandin synthesis is disfavored because prostaglandins also beneficially maintain the digestive tract lining. In the absence of prostaglandins, a propensity for ulcers and similar digestive problems can develop. This is particularly problematic for people suffering from conditions such as arthritis, the treatment of which generally requires long-term use of relatively large doses of anti-inflammatory agents.
The cyclooxygenase enzymes are reviewed by Williams, C. S. and R. N. DuBois, "Prostaglandin endoperoxide synthase: Why two isoforms?" Am. J. Physiol. 270 (Gastrointest. Liver Physiol. 33):G393-G400 (1996), incorporated herein by reference in its entirety. Briefly, cyclooxygenase exists in at least two different enzyme isoforms (Simmons et al., P.N.A.S. U.S.A. 86:1178-1182 (1989)), designated-Cox-1 and Cox-2. Cox-1 is involved in synthesizing housekeeping prostaglandins that function to maintain the digestive tract lining. In contrast, Cox-2 catalyzes the synthesis of prostaglandins that cause inflammation and pain, but does not appear to catalyze housekeeping prostaglandins. Both Cox-1 and Cox-2 are involved in producing precursors for several prostanoids including PGE.sub.2.
Cox-1 is expressed constitutively at relatively stable levels in many tissues, whereas Cox-2 expression can be induced by a variety of chemicals, including, but not limited to, lipopolysaccharides, phorbal esters, interleukin-1, tumor necrosis factor, human chorionic gonadotropin, and platelet activating factor. As a result of this distinction, one can characterize the relative contribution of each isoform to the overall PGE.sub.2 level by comparing basal PGE.sub.2 levels to the levels after induction.
Because existing drugs that bind both Cox-1 and Cox-2 can cause significant undesired gastric side effects, considerable attention has been directed toward developing pain relief medications that specifically inhibit Cox-2 enzyme activity without affecting Cox-1 enzyme activity. Recently, the Food and Drug Administration approved one such medication, Celebrex, only for the treatment of arthritis pain, pending further studies. Preliminary results suggest that Celebrex provides pain relief and reduces inflammation without causing stomach problems. Unfortunately, Celebrex is expensive.
Accordingly, there is currently a strong interest in developing pharmaceuticals and therapies that reduce inflammation and provide pain relief without causing associated stomach problems.
Conjugated linoleic acid reduces liver and serum PGE.sub.2 levels in rats fed a diet containing 1% CLA (Sugano, et al. Nutritional Biochem. 8:38-43, 1997). Liu et al. (Cancer Lett. 127:15-22, 1998) suggested that CLA inhibits PGE.sub.2 synthesis by cyclooxygenase by competing with the enzyme's substrate, arachidonic acid. It was not known whether conjugated linoleic acids inhibit both Cox-1 and Cox-2.